GB2197589A

GB2197589A - Stimulating hair growth

Info

Publication number: GB2197589A
Application number: GB08727113A
Authority: GB
Inventors: Jean-Francois Grollier
Original assignee: LOreal SA
Current assignee: LOreal SA
Priority date: 1986-11-19
Filing date: 1987-11-19
Publication date: 1988-05-25
Anticipated expiration: 2007-11-19
Also published as: CA1297411C; JPS63135316A; GB8727113D0; IT8767993A0; NL8702772A; IT1211544B; FR2606635A1; DE3739207A1; CH672423A5; GB2197589B; FR2606635B1; ES2009222A6; LU86672A1; BE1000621A3

Description

2 19 7 58) 9 1 - 1 COMPOSITION FOR INDUCING AND STIMULATING HAIR GROWTH

AND REDUCING HAIR LOSS The present invention relates to compositions for inducing and stimulating hair growth and reducing hair loss based on alkylenediaminoquinazoline derivatives.

Man has from 100,000 to 150,000 hairs on the head and it is normal to lose 50 to 100 hairs daily. The retention of the growth of hair on the head results essentially from the fact that a hair is subject to a cycle known as a pilary cycle, during which a hair forms, grows and falls out before being replaced by a new hair which appears in the same follicle.

Three phases are successively observed in the pilary cycle, namely the anagen phase, the catagen phase and the telogen phase.

During the first or anagen phase the hair undergoes active growth associated with an intensive metabolic activity in the bulb region.

The second or catagen phase is transitory and is marked by a slowing down of the mitotic activity. Dur ing this phase, the hair undergoes an involution, the follicle atrophies and its dermal implantation appears increasingly high.

The final or telogen phase corresponds to a period of rest of the follicle and the hair ends by falling out, pushed by a nascent anagen hair.

- 2 This process of continual physical renewal undergoes a natural evolution in the course of aging; the hair becomes finer and the cycles become shorter.

Alopecia takes place when physical renewal is accelerated or perturbed, that is to say that the phases of growth are shortened, the transition of the hair to the telogen phase is more frequent and hair falls out in increasing numbers; the successive growth cycles produce hair which is increasingly finer and increasingly shorter, and the hair is gradually transformed to an unpigmented down. This phenomenon can lead to baldness.

Many factors contribute to the pilary cycle and may give rise to more or less pronounced alopecia, for example alimentary, endocrine and nervous factors. The variation of the different categories of hairs can be determined by a trichogram.

In the cosmetic and pharmaceutical industries research has been carried out for many years into compositions to eliminate or reduce alopecia and especially to permit hair growth to be induced or stimulated.

Compounds such as 6-amino-1,2-dihydro-l-hydroxy2-imino-4piperidinopyrimidine and derivatives thereof have already been proposed. Such compounds are described particularly in US-A-4,139,619.

In patent WO-A-83/02,558 it has been proposed to combine retinoids with these compounds.

We have found that certain alkylenediaminequinazoline derivatives can, surprisingly, induce and stimulate hair growth and reduce hair loss.

These compounds are known and have been described in particular in French Certificate of Addition applications No. 2,466,462 and 2,468,595. They are particularly known for their therapeutic properties, especially in the cardiovascular field, as antihypertensives.

We have found that these compounds, when employed topically, exhibit an activity on new growth of hair and enable the growth of hair to be induced or stimulated and reduce its loss.

The present invention provides a composition suitable for inducing and stimulating hair growth and retarding hair loss which comprises, in a cosmetically or pharmaceutically acceptable medium, at least one alkylenediaminoquinazoline derivative of formula:

__,__1-CnH2n- COR CH30 2 CH 3 0 2 (1) in which:

R, and R 2 denote, independently of each other, hydrogen, an alkyl group containing 1 to 4 carbon atoms or a benzyl group; n is 2, 3 or 4; and R denotes a C 3- C 6 cycloalkyl group, a group of formula:

-- (CE2) q 0) wherein q is 0, 1 or 2, a group of formula:

- 1 o r ( I I I) or a group of formula:

IP j CH2)m 4 - 5 wherein m is 0, 1 or 2 and p is 0, 1 or 2; p or a pharmaceutically or cosmetically acceptable acid addition salt thereof.

The compounds which are particularly preferred are those in which n is 3, R, denotes hydrogen or a methyl group, R 2 denotes a methyl or benzyl group, and R denotes a tetrahydrofuryl, cyclopentyl, cyclopropyl, dihydrobenzofuryl or benzofuryl group.

The compound which is particularly preferred is that in which n is 3, R 2 denotes a methyl group, R, denotes hydrogen and R denotes a tetrahydrofuryl group.

The compositions according to the invention, which are suitable for topical application, generally comprise the compound of formula (I) in a proportion of from 0.01 to 10%, preferably from 0.1 to 5%, relative to the total weight of the composition.

A particularly preferred composition comprises NI-(4-amino-6,7-dimethoxy2-quinazolyl)-NI-methylN"-(2-tetrahydrofuroyl)propylenediamine monohydrochloride in a proportion of from 0.1 to 5% by weight relative to the total weight of the composition.

According to an especially advantageous embodiment of the invention, the composition may also comprise a pyrimidine derivative having an effect on new hair growth, for example one disclosed in US-A-4,139,619 - 6 and more particularly 6-amino-1,2-dihydro-l-hydroxy-2imino-4- piperidinopyrimidine, also known as minoxidil, or a retinoid, such as one described in WO-82/02,833, or a combination thereof.

Preferred retinoids are all-trans retinoic acid and 13-cis retinoic acid and their physiologically (pharmaceutically or cosmetically) acceptable salts or esters.

When present, these compounds are generally employed in a proportion of from 0.01 to 10% by weight, in the case of the pyrimidine derivatives, and from 0.001 to 2% by weight in the case of the retinoids, relative to the total weight of the composition.

These compounds may be used in the composition comprising the compound of formula (1), or may be applied to the hair or scalp separately, either simultaneously or sequentially, before or after the composition comprising the compound of formula (I).

The composition according to the present invention may, for example, be in the form of a lotion, emulsion, cream or gel or may be pressurized in an aerosol. It may, for example, be applied in a treatment which may or may not be followed by rinsing, or may be used in the form of a shampoo.

The cosmetically or pharmaceutically acceptable medium, such as a physiologically acceptable medium, may, for example, be an alcoholic or an aqueous medium. The medium may or may not be thickened and may, for example, comprise one or more cosmetically or pharmaceutically acceptable solvents.

The solvent is preferably a C1-C 4 alcohol such as ethyl alcohol, isopropyl alcohol or tert-butyl alcohol, an alkylene glycol such as propylene glycol or a mono- or dialkylene glycol alkyl ether such as ethylene glycol monoethyl ether, propylene glycol monomethyl ether or diethylene glycol monoethyl ether.

The composition may comprise other adjuvants usually employed in the cosmetic or pharmaceutical field in topical compositions such as a surface-active agent, a thickener, a preservative or an alkalifying or acidifying agent. The pH of the composition is generally from 3 to 9 and preferably from 5 to 8.

A thickening or gelling agent may be used and is, for example, a heterobiopolysaccharide such as one containing mannose, glucose, glucuronic or galacturonic units in its chain, and more particularly xanthan gum or a scleroglucane.

8 - Examples of these products are Keltrol T or TF, Ke1zan S, Ke1zan K9C57, Ke1zan K8B12, and Ke1zan K3B130, marketed by Kelco, Rhodopol 23 and 23SC or Rhodigel 23 marketed by Rhone Poulenc, Deuteron XG marketed by Schoner GmbH, and Actigum CX9, CS11 or C56 marketed by CECA/SATIA; other heterobiopolysaccharides which can be employed are described in EP-A-23, 397, GB-A-2,058,106, GB-A-2,058,107, US-A-4,454,316, EP-A-64,354 and DE-A3,224,547.

other gelling agents are, for example, cellulose derivatives such as methyl cellulose, hydroxymethyl cellulose, carboxymethyl cellulose, hydroxybutyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl hydroxyethyl cellulose or methyl hydroxypropyl cellulose. These thickening or gelling agents are preferably employed in a proportion of from 0.5 to 5%, in particular from 1 to 3%, by weight relative to the total weight of the composition.

Other thickening agents which can be employed are, for example, polyacrylic acids crosslinked with a polyfunctional agent, such as Carbopol marketed by Goodrich or the thickeners resulting from an ionic interaction of a cationic polymer which is a copolymer of cellulose or of a cellulose derivative grafted with a quaternary ammonium salt of a watersoluble monomer and of a carboxylic anionic polymer. Among the latter are, for example, thickeners - 9 resulting from the interaction of a hydroxyalkyl cellulose copolymer grafted by a radical route with a methacryloylethyl trimethylammonium, methacrylamidopropyltrimethylammonium or dimethy1diallylammonium salt and of a carboxylic anionic polymer which is a methacrylic acid homopolymer, a copolymer of methacrylic acid with a monomer which is a C1-C 4 alkyl acrylate or methacrylate, acrylamide derivative, maleic acid, CI-C 4 alkyl monomaleate, vinylpyrrolidone or a copolymer of ethylene and maleic anhydride. The weight ratio of the cationic polymer to the carboxylic anionic polymer is generally from 1:5 to 5:1.

The thickening agent is generally employed in a proportion of from 0.5 to 2%, preferably from 0.7 to 1.5%, by weight relative to the total weight of the composition.

The treatment for combatting hair loss consists principally in applying a composition of the present invention to the alopecic regions of the subject's scalp and hair, for example after washing the scalp or the hair with a shampoo or shortly after a shampoo. The preferred method of application consists in applying 1 to 2 g of the composition of the present invention to the alopecic region with a surface area of 200 to 300 CM2 of the scalp, at a frequency of one to two applications daily for 1 to 7 days a week.

- The effectiveness of the treatment may, for example, be monitored once a month with a phototrichogram.

we have found a significant increase in the total density of hair, with an increase in the amount of hair in the anagen phase and a decrease in the amount of hair in the telogen phase after 2 months' treatment.

The present invention also provides the use of a compound of formula (I) in the preparation of a composition for inducing and stimulating hair growth and retarding hair loss.

The treatment process may have the characteristics of a cosmetic process insofar as it permits the hair and the scalp to be cared for within the cosmetic meaning of the term, that is to say to impart to them the substances which they lack and to beautify them.

Furthermore, the process may have the characteristics of a therapeutic treatment insofar as the active substance has a therapeutic activity in respect of the biological mechanisms of the pilary cycle.

The following Examples further illustrate the invention.

1 EXAMPLE 1

The lotion which is active in respect of hair growth and reduction in its loss, with the following composition, is prepared: - NI-(4-amino-6,7diemethoxy-2-quinazolyl)-Ny-methyl-N"(2-tetrahydrofuroyl)propylenediamine monohydrochloride 19 - Preservative, perfume q.s.

- Water q.s. 100g The activity of the composition for stimulating new growth of hair relative to a placebo is assesed by applying 1 ml of this composition at a rate of one application daily to an alopecic region of the scalp of five subjects whose average age is 40. After a dew months of treatment, the composition effectively improves the state of the hair.

EXAMPLE 2

The lotion which is active in respect of hair growth and reduction in its lossf with the following composition, is prepared: - NI-(4-amino-6,7dimethoxy-2-quinazolyl)-NI-methyl-N"(cyclopentylcarbonyl)propylenediamine monohydrochloride 2g - Preservative, perfume q.s.

- Water q.s. 100g EXAMPLE 3

A gel which is active in respect of stimulating hair growth and retarding its loss, with the following composition, is prepared: - N'-(4-amino-6,7dimethoxy-2-quinazolyl)-N'-methyl-N"(2-tetrahydrofuroyl)propylenediamine monohydrochloride 3g - Heteropolysaccharide sold by Kelco under the trade name Keltrol 1 - Isopropyl alcohol Water q. s.

EXAMPLE 4

A gel which is active in respect of stimulating hair growth and retarding its loss, with the following composition, is prepared: - Nl-(4-amino-6,7dimethoxy-2-quinazolyl)-NI-methylN"-(2-tetrahydrofuroyl)propylenediamine monohydrochloride Hydroxypropyl cellulose sold by Hercules under the trade name Klucel G - Isopropyl alcohol q. s.

lg 30g 100g 2g 3g 100g - 13 EXAMPLE 5 A lotion which is active in respect of stimulating hair growth and retarding its loss, with the following composition, is prepared: - NI-(4amino-6,7-dimethoxy-2-quinazolyl)-NImethyl-N"-(2tetrahydrofuroyl)propylene- diamine monohydrochloride 3g - Propylene glycol 20g - Ethyl 52g - Water q. s. 100g When applied for 2 months at a rate of one application per day to the scalp, an increase of the order of 15% in hair density, accompanied by a significant increase in the hair in an anagen phase and a decrease in the hair in a telogen phase, is found.

EXAMPLE 6

A lotion which is active in respect of stimulating hair growth and retarding its loss, with the following composition, is prepared: - NI-(4amino-6,7-dimethoxy-2-quinazolyl)-Nymethyl-N"-(2tetrahydrofuroyl)propylene- diamine monohydrochloride 1.5g 1 q. s.

1. 5g 20g 50g 100g EXAMPLE 7

A lotion which is active in respect of stimulating hair growth and retarding its loss, with the following composition, is prepared: - NI-(4amino-6,7-dimethoxy-2-quinazolyl)-NImethyl-N"-(2tetrahydrofuroyl)propylene- diamine monohydrochloride 0.3g Ethyl alcohol 95g - Propylene glycol q.s. 100g EXAMPLE 8

A gel which is active in respect of stimulating hair growth and retarding its loss, with the following composition, is prepared: - Nl-(4-amino-6,7dimethoxy-2-quinazolyl)-NI methyl-N"-(2-tetrahydrofuroyl)propylenediamine monohydrochloride - Trans retinoic acid - Ethyl alcohol 0.75g 0.0125g 5Og - is - Polyacrylic acid sold by Goodrich under the name of Carbopol 940 Water Preservative Triethanolamine Propylene glycol 1g 139 q. s. q. s. pH 5 q. s.

100a

Claims

1. A composition suitable for inducing and stimulating hair growth and retarding hair loss, which comprises, in a cosmetically or pharmaceutically acceptable medium, at least one alkylenediaminoquinazoline derivative of formula:

A-CnH2n- COR C1130 A2 CH 3 0 in which R, and R 2 denote, independently of each other, hydrogen, an alkyl group containing 1 to 4 carbon atoms or a benzyl group; n is 2, 3 or 4; and R denotes a C 3- C 6 cycloalkyl group, a group of formula:

(I) CH2) q -±- 0 wherein q is 0, 1 or 2, a group of formula:

- 1 0 r - le (111) (11) 1 1 lil;-, (IV) I - 17 or a group of formula - -) CR2) M 1 (V) I p wherein m is 0, 1 or 2 and p is 0, 1 or 2; or a pharmaceutically or cosmetically acceptable acid addition salt thereof.

2. A composition according to claim 1, wherein n is 3, R, denotes hydrogen or a methyl group, R2 denotes a methyl or benzyl group and R denotes a tetrahydrofuryl, cyclopentyl, cyclopropyl, dihydrobenzofuryl or benzofuryl group.

3. A composition according to claim 2, wherein R 2 denotes a methyl group, R, denotes hydrogen and R denotes a tetrahydrofuryl group.

4. A composition according to any one of claims 1 to 3, wherein the compound of formula (I) is present in a proportion of from 0.01 to 10% by weight relative to the total.weight of the composition.

5. A composition according to any one of claims 1 to 4, wherein the pharmaceutically or cosmetically acceptable medium is a hydroalcoholic, aqueous or alcoholic medium.

i 18 -

6. A composition according to any one of claims 1 to 5, which is in the form of a gel which comprises a gelling agent, which is a heterobiopolysaccharide or a cellulose derivative.

7. A composition according to any one or claims 1 to 6, which comprises a thickener which is an acrylic acid polymer crosslinked with a polyfunctional agent of a thickener resulting from an ionic interaction of a cationic polymer which is a copolymer of cellulose or of a cellulose derivative grafted with a quaternary ammonium salt of a water-soluble monomer and of a carboxylic anionic polymer.

8. A composition according to any one of claims 1 to 7, which comprises a pyrimidine derivative having an effect on new hair growth or a retinoid or a mixture thereof.

9. A composition according to claim 8, wherein the pyrimidine derivative is 6-amino-1,2-dihydro-l-hydroxy2-imino-4-piperidinopyrimidine.

10. A composition according to claim 8 or 9, wherein the retinoid is alltrans retinoic acid or 13-cis retinoic acid, or a physiologically acceptable salt or ester thereof.

11. A composition according to any one of claims 8 to 10 wherein the pyrimidine derivative is present in a proportion of from 0.01 to 10% by weight relative to the total weight of the composition.

12. A composition according to any one of claims 8 to 11, wherein the retinoid is present in a proportion of from 0.001 to 2% by weight relative to the total weight of the composition.

13. A composition according to claim 1 substantially as described in any one of the Examples.

14. A multi component kit suitable for inducing and stimulating hair growth and retarding hair loss, comprising a component (A) comprising a composition as defined in any one of claims 1 to 7, and a separate component (B) comprising, in'a physiologically acceptable medium, a pyrimidine derivative which promotes hair growth, or a retinoid or a mixture thereof, the components (A) and (B) being suitable for sequential or simultaneous application to the hair or scalp.

15. A kit according to claim 14, wherein the pyrimidine derivative is 6amino-1,2-dihydro-l-hydroxy-2imino-4-piperidinopyrimidine, and the retinoid is all-trans retinoic acid or 13-cis retinoic acid, or a physiologically acceptable salt or ester thereof.

16. A kit according to claim 14 comprising a composition (A) substantially as described in any one of Examples 1 to 5.

17. Use of an alkylenediaminoquinazoline derivative of formula (I) as defined in any one of claims 1 to 3 in the preparation of a medicament to induce and stimulate hair growth and to retard hair loss.

18. A process for a cosmetic treatment of the hair, wherein at least one composition as defined in any one of claims 1 to 13 or, components (A) and (B) from a kit as defined in any one of claims 14 to 16 is applied to the hair or the scalp.